Tubby-like proteins (TULPs) comprise a family of proteins found in all multicellular organisms. These molecules are characterized by the presence of a conserved carboxy-terminal "tubby domain" that does not exhibit sequence homology to other known proteins. Genetic mutation of tubby or other TULPs often leads to one or more of three disease phenotypes: (1) obesity - from which the name "tubby" is derived, (2) retinal degeneration, and (3) hearing loss. The disease phenotypes associated with mutations in tubby-like proteins clearly indicate a vital role for these molecules in normal tissue function. While the expression pattern of each family member is distinctive, tubby proteins are found mainly in the nervous system, and all known human tubby proteins are expressed in the retina. Mutation of the TULP1 gene is the cause of retinitis pigmentosa type 14 (about 5 percent of inherited RP cases), and the human TULP2 gene maps within the minimal identified region for the cone-rod retinal dystrophy locus on chromosome 19. Furthermore, tubby mutants bear a remarkable similarity to several human syndromes that result in combined sensorineural hearing loss and retinal degradation, accompanied by obesity. Despite the clear medical importance of tubby-like proteins, no biochemical function has yet been ascribed to any member of this protein family. In order to identify the biochemical function of tubby and other TULPs -and to thus understand their role in disease - we will use X-ray crystallography to determine the high-resolution three-dimensional structure of tubby. We will identify a function for tubby based on structural similarities to other known proteins, by identification of chemical functionalities such as active sites or cofactors, and by the application of concomitant cell biological and biochemical studies, including cellular and sub-cellular localization studies. This is a model problem for a "structural genomics" approach to identification of function for a medically relevant protein. This approach relies on structural information, phenotype data, and classical biology approaches enabled by the availability of pure protein. This type of approach should be greatly facilitated by the recent massive expansion of the database of three-dimensional structures.